Preparation method for dual sustained-release dapagliflozin tablet

Abstract

Provided is a preparation method for a dual sustained-release dapagliflozin tablet. The dapagliflozin tablet consists of an enteric-soluble inner core, a gastric-soluble middle core, and a coating. The gastric-soluble middle core consists of the following raw and auxiliary materials, in percentage by weight: 5-7% of dapagliflozin, 10% of voglibose, 69-73% of a microcrystalline cellulose complex, 2-4% of a disintegrating agent, and 10% of an HPMC coating solution; and the enteric-soluble inner core consists of the following raw and auxiliary materials, in percentage by weight: 5-7% of dapagliflozin, 8% of Yuanzhen sugar, 63-77% of a microcrystalline cellulose complex, 4-8% of a disintegrating agent, 8% of an HPMC coating solution, and 6% of alginic acid. The prepared dapagliflozin tablet has the advantages of high dissolution rates of the pharmaceutical ingredients, good release effect, and low pressure on the kidneys.

Description

A preparation method of dual sustained-release dapagliflozin tablets Technical Field

[0001] The invention relates to a preparation method of a dual sustained-release dapagliflozin tablet, belonging to the field of pharmaceutical preparations. Background Art

[0002] Dapagliflozin, a drug developed in collaboration between Bristol-Myers Squibb and AstraZeneca, is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to treat type 2 diabetes. It inhibits sodium-glucose transporter 2 to prevent glucose from being reabsorbed into the blood, allowing excess glucose to be excreted from the body through urine, thereby improving blood sugar control without increasing insulin secretion. Used alone or in combination with other drugs, it can significantly reduce HbA1c and fasting blood sugar in patients with type 2 diabetes.

[0003] Patent document CN107714667A discloses a method for preparing a dapagliflozin composition, which contains multiple ingredients in specific proportions and is intended to optimize the solubility of dapagliflozin. However, although the patent aims to solve the dissolution problem, according to the data in Table 1 of the document, the prepared dapagliflozin preparation was not completely dissolved after 60 minutes, affecting the absorption efficiency of the drug and thus failing to achieve the ideal therapeutic effect. Therefore, although the patent provides an innovative composition formula, there is still room for improvement in ensuring complete dissolution of the drug and maximizing the therapeutic effect.

[0004] Patent document CN106924208A discloses a compound dapagliflozin metformin sustained-release tablet and its preparation method. Although it is proposed that dapagliflozin be mixed with the filler mannitol to achieve the effect of rapid hypoglycemic effect, there are also obvious problems. Although the diuretic effect of mannitol can assist in lowering blood sugar, considering that diabetic patients themselves are prone to symptoms of polydipsia and polyuria, this mixing will undoubtedly further increase the burden on the kidneys. In addition, for patients with pyelonephritis, bladder diseases and genital infections, this mixing may significantly aggravate its side effects and cause adverse effects on physical health. What is more serious is that this combination is also likely to cause water and electrolyte disorders in the body, further increasing the risk of treatment. Therefore, although the mixing of dapagliflozin and mannitol may bring a certain hypoglycemic effect, its potential risks and side effects cannot be ignored, and it is necessary to be extremely cautious when using it.

[0005] Therefore, there is an urgent need to find a synthesis method that has high solubility and good release effect of drug ingredients and less pressure on the kidneys. Summary of the Invention

[0006] In view of the defects existing in the above-mentioned prior art, the present invention provides a method for preparing a dual-sustained-release dapagliflozin tablet, which solves the problem of improving the drug dissolution rate and reducing kidney pressure.

[0007] The object of the present invention is achieved by the following technical scheme: a method for preparing a dual sustained-release dapagliflozin tablet, wherein the dapagliflozin tablet is composed of an enteric-coated inner core, a gastric-coated middle core and a coating.

[0008] The gastric-soluble core is composed of the following raw materials and auxiliary materials in the following weight percentages: 5-7% dapagliflozin, 10% voglibose, 69-73% microcrystalline cellulose complex, 2-4% disintegrant, and 10% HPMC coating solution;

[0009] The enteric-coated core is composed of the following raw materials and auxiliary materials in the following weight percentages: 5-7% dapagliflozin, 8% guanidine sugar, 63-77% microcrystalline cellulose complex, 4-8% disintegrant, 8% HPMC coating solution, and 6% alginic acid.

[0010] In the preparation method of the above-mentioned dapagliflozin tablets, the method comprises the following steps:

[0011] S1: The raw material dapagliflozin is crushed and sieved, and then mixed with voglibose, microcrystalline cellulose complex, disintegrant and other excipients. The granules are wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules are then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine granules.

[0012] S2: The raw material dapagliflozin is crushed and sieved, and then mixed with excipients such as guanidine sugar, microcrystalline cellulose complex, and disintegrants. The granules are wet granulated to an average particle size of 0.2 mm to 0.8 mm. The granules are then coated with HPMCP coating solution by spraying and dried to obtain dapagliflozin enteric-coated fine granules.

[0013] S3: tableting the dapagliflozin enteric-coated fine granules prepared in step S2, coating the tablets with an aqueous solution of alginic acid by dipping, and drying to obtain the dapagliflozin enteric-coated core;

[0014] S4: The dapagliflozin enteric-coated core prepared in step S3 is wrapped with the dapagliflozin gastric-soluble fine particles prepared in step S1 to form a gastric-soluble middle core and tablets are compressed. The tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets.

[0015] In the above-mentioned method for preparing dapagliflozin tablets, preferably, the microcrystalline cellulose complex is one of a lactose-microcrystalline cellulose complex and a silicified microcrystalline cellulose complex.

[0016] As the most preferred, the microcrystalline cellulose composite has good fluidity and compressibility, can improve the formability of the preparation, has good physical and chemical stability, and protects the drug from moisture and other environmental factors.

[0017] In the above-mentioned preparation method of dapagliflozin tablets, preferably, in the lactose-microcrystalline cellulose complex, the weight ratio of lactose to microcrystalline cellulose is 70-75:25-30; in the silicified microcrystalline cellulose complex, the weight ratio of silicon dioxide to microcrystalline cellulose is 2:98.

[0018] As the most preferred, the lactose-microcrystalline cellulose complex can regulate the release rate and release pattern of the drug, thereby achieving better drug efficacy, and has good compressibility during the tableting process, which helps to prepare strong and easy-to-take tablets.

[0019] In the above-mentioned preparation method of dapagliflozin tablets, preferably, the raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water.

[0020] As the most preferred, the addition of polyethylene glycol and ethyl cellulose can increase the viscosity of the coating solution, which helps to improve the uniformity and quality of the coating. Montmorillonite can increase the adhesion of the coating solution to the tablet surface, which helps to form a uniform coating layer.

[0021] In the above-mentioned method for preparing dapagliflozin tablets, preferably, the mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in the dapagliflozin tablets is 3:7.

[0022] As the most preferred method, different mass ratios of gastric-soluble and enteric-soluble fine particles are used to adjust the release of dapagliflozin and the efficiency of its absorption by the human body in different parts of the body. The stomach absorbs dapagliflozin less effectively, so the gastric-soluble portion is smaller in amount and can dissolve rapidly in the stomach, providing rapid release and initial absorption, while the enteric-soluble portion is larger in amount and is slowly released in large quantities in the intestine to improve the absorption effect.

[0023] In the above-mentioned method for preparing dapagliflozin tablets, preferably, the disintegrant is one of cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone.

[0024] In the above-mentioned method for preparing dapagliflozin tablets, preferably, the silicon dioxide is mesoporous silicon dioxide with a particle diameter of 350-450 nm.

[0025] As the most preferred, mesoporous silica has a larger specific surface area and pore volume, which is helpful for drug loading and release, can improve drug solubility, achieve better release characteristics, and enhance bioavailability.

[0026] In the above-mentioned method for preparing dapagliflozin tablets, preferably, the average particle size of the microcrystalline cellulose composite is 90-150 μm.

[0027] As the most preferred, small-particle microcrystalline cellulose complex has good fluidity, which is convenient for drug preparation. At the same time, the smaller particle size helps to improve the solubility of the microcrystalline cellulose complex, accelerate the release rate of the drug, improve the bioavailability, and thus enhance the efficacy of the drug.

[0028] In summary, the present invention has the following advantages compared with the prior art:

[0029] 1. In the scheme of the present invention, voglibose and dapagliflozin are used in combination to replace metformin. Voglibose, as an α-glucosidase inhibitor, can reduce the rate of glucose absorption in the intestine. At the same time, the absorption and action organs of voglibose are not in the liver and kidneys, avoiding the pressure on the kidneys caused by the use of metformin. Voglibose inhibits glucose absorption, and dapagliflozin promotes blood sugar excretion, forming a complementary pharmacological effect and enhancing the hypoglycemic effect.

[0030] 2. In the solution of the present invention, Yuanzhen sugar will not have a significant impact on blood sugar after being absorbed in the intestine. At the same time, it can slow down the abnormal blood sugar caused by dapagliflozin being absorbed by the human body. Dapagliflozin lowers blood sugar levels by promoting excretion. Yuanzhen sugar has lower calories than glucose and has less impact on blood sugar.

[0031] 3. In the scheme of the present invention, the dapagliflozin tablets are released in layers through the gastric-soluble middle core and the enteric-soluble inner core, so that the human organs dissolve and absorb dapagliflozin in segments. At the same time, due to the different masses, the release of dapagliflozin and the efficiency of its absorption by the human body can be adjusted in different parts. The stomach absorbs dapagliflozin less effectively, so the gastric-soluble part is small in amount and can dissolve quickly in the stomach, providing rapid release and initial absorption, while the enteric-soluble part is large in amount and slowly released in the intestine to improve the absorption effect, forming a non-centralized absorption and achieving a long-term sustained-release effect, effectively reducing the dosage of dapagliflozin, and effectively alleviating its adverse symptoms while ensuring the efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG1 is a dissolution rate measurement result of the present invention. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments. Example 1

[0034] Prepare the following raw materials and excipients by weight: 5% dapagliflozin, 10% voglibose, 73% lactose-microcrystalline cellulose complex, 2% croscarmellose sodium, and 10% HPMC coating solution;

[0035] The raw material dapagliflozin was crushed and sieved, and then mixed with voglibose, lactose-microcrystalline cellulose complex, cross-linked carboxymethyl cellulose sodium and other excipients. The granules were wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules were then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine granules.

[0036] Prepare the raw materials and excipients according to the following weight components: 5% dapagliflozin, 8% guanidine sugar, 69% lactose-microcrystalline cellulose complex, 4% cross-linked polyvinylpyrrolidone, 8% HPMC coating solution, and 6% alginic acid;

[0037] The raw material dapagliflozin was crushed and sieved, and then mixed with excipients such as guanidine sugar, lactose-microcrystalline cellulose complex, and cross-linked polyvinylpyrrolidone. The wet granulation method was adopted, and the average particle size of the granules was distributed between 0.2 mm and 0.8 mm. The granules were then coated with HPMCP coating solution by spraying, and the dapagliflozin enteric-coated fine granules were obtained after drying.

[0038] The dapagliflozin enteric-coated fine granules are tableted, the tablets are coated with an aqueous solution of alginic acid by dipping, and the tablets are dried to obtain the dapagliflozin enteric-coated core;

[0039] The dapagliflozin enteric-coated inner core is coated with dapagliflozin gastric-soluble fine particles to form a gastric-soluble middle core, which is then compressed into tablets, and the tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets;

[0040] In the lactose-microcrystalline cellulose complex, the weight ratio of lactose to microcrystalline cellulose is 70-75:25-30;

[0041] The average particle size of the microcrystalline cellulose composite was 90–150 μm;

[0042] The raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water;

[0043] The mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in dapagliflozin tablets is 3:7. Example 2

[0044] Prepare the following raw materials and excipients by weight: 7% dapagliflozin, 10% voglibose, 69% lactose-microcrystalline cellulose complex, 4% croscarmellose sodium, and 10% HPMC coating solution;

[0045] The raw material dapagliflozin was crushed and sieved, and then mixed with voglibose, lactose-microcrystalline cellulose complex, cross-linked carboxymethyl cellulose sodium and other excipients. The granules were wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules were then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine granules.

[0046] Prepare the raw materials and excipients according to the following weight components: 7% dapagliflozin, 8% guanidine sugar, 63% lactose-microcrystalline cellulose complex, 8% cross-linked polyvinylpyrrolidone, 8% HPMC coating solution, and 6% alginic acid;

[0047] The raw material dapagliflozin was crushed and sieved, and then mixed with excipients such as guanidine sugar, lactose-microcrystalline cellulose complex, and cross-linked polyvinylpyrrolidone. The wet granulation method was adopted, and the average particle size of the granules was distributed between 0.2 mm and 0.8 mm. The granules were then coated with HPMCP coating solution by spraying, and the dapagliflozin enteric-coated fine granules were obtained after drying.

[0048] The dapagliflozin enteric-coated fine granules are tableted, the tablets are coated with an aqueous solution of alginic acid by dipping, and the tablets are dried to obtain the dapagliflozin enteric-coated core;

[0049] The dapagliflozin enteric-coated inner core is coated with dapagliflozin gastric-soluble fine particles to form a gastric-soluble middle core, which is then compressed into tablets, and the tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets;

[0050] In the lactose-microcrystalline cellulose complex, the weight ratio of lactose to microcrystalline cellulose is 70-75:25-30;

[0051] The average particle size of the microcrystalline cellulose composite was 90–150 μm;

[0052] The raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water;

[0053] The mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in dapagliflozin tablets is 3:7. Example 3

[0054] Prepare the following raw materials and excipients by weight: 6% dapagliflozin, 10% voglibose, 71% lactose-microcrystalline cellulose complex, 3% croscarmellose sodium, and 10% HPMC coating solution;

[0055] The raw material dapagliflozin was crushed and sieved, and then mixed with voglibose, lactose-microcrystalline cellulose complex, cross-linked carboxymethyl cellulose sodium and other excipients. The granules were wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules were then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine granules.

[0056] Prepare the raw materials and excipients according to the following weight components: 6% dapagliflozin, 8% guanidine sugar, 66% lactose-microcrystalline cellulose complex, 6% cross-linked polyvinylpyrrolidone, 8% HPMC coating solution, and 6% alginic acid;

[0057] The raw material dapagliflozin was crushed and sieved, and then mixed with excipients such as guanidine sugar, lactose-microcrystalline cellulose complex, and cross-linked polyvinylpyrrolidone. The wet granulation method was adopted, and the average particle size of the granules was distributed between 0.2 mm and 0.8 mm. The granules were then coated with HPMCP coating solution by spraying, and the dapagliflozin enteric-coated fine granules were obtained after drying.

[0058] The dapagliflozin enteric-coated fine granules are tableted, the tablets are coated with an aqueous solution of alginic acid by dipping, and the tablets are dried to obtain the dapagliflozin enteric-coated core;

[0059] The dapagliflozin enteric-coated inner core is coated with dapagliflozin gastric-soluble fine particles to form a gastric-soluble middle core, which is then compressed into tablets, and the tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets;

[0060] In the lactose-microcrystalline cellulose complex, the weight ratio of lactose to microcrystalline cellulose is 70-75:25-30;

[0061] The average particle size of the microcrystalline cellulose composite was 90–150 μm;

[0062] The raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water;

[0063] The mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in dapagliflozin tablets is 3:7. Example 4

[0064] Prepare the following raw materials and excipients by weight: 5% dapagliflozin, 10% voglibose, 73% silicified microcrystalline cellulose complex, 2% croscarmellose sodium, and 10% HPMC coating solution;

[0065] The raw material dapagliflozin was crushed and sieved, and then mixed with voglibose, silicified microcrystalline cellulose complex, cross-linked sodium carboxymethyl cellulose and other excipients. The granules were wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules were then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine particles.

[0066] Prepare the raw materials and excipients according to the following weight components: 5% dapagliflozin, 8% guanidine sugar, 69% silicified microcrystalline cellulose complex, 4% cross-linked polyvinylpyrrolidone, 8% HPMC coating solution, and 6% alginic acid;

[0067] The raw material drug dapagliflozin was crushed and sieved, and then mixed with excipients such as guanidine sugar, silicified microcrystalline cellulose complex, and cross-linked polyvinylpyrrolidone. The wet granulation method was used to obtain a granulation particle size with an average distribution of 0.2 mm to 0.8 mm. The granulation was then coated with HPMCP coating liquid by spraying. After drying, dapagliflozin enteric-coated fine granules were obtained.

[0068] The dapagliflozin enteric-coated fine granules are tableted, the tablets are coated with an aqueous solution of alginic acid by dipping, and the tablets are dried to obtain the dapagliflozin enteric-coated core;

[0069] The dapagliflozin enteric-coated inner core is coated with dapagliflozin gastric-soluble fine particles to form a gastric-soluble middle core, which is then compressed into tablets, and the tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets;

[0070] In the silicified microcrystalline cellulose composite, the weight ratio of silicon dioxide to microcrystalline cellulose is 2:98;

[0071] Silica uses mesoporous silica with a particle diameter of 350~450nm;

[0072] The average particle size of the microcrystalline cellulose composite was 90–150 μm;

[0073] The raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water;

[0074] The mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in dapagliflozin tablets is 3:7.

[0075] Comparison results

[0076] The dapagliflozin tablets prepared in Examples 1 to 4 were taken respectively, and the control group was a commercially available dapagliflozin tablet. 900 mL of hydrochloric acid solution with a pH of 1.2 was used as the dissolution medium. The paddle method was used at 50 r / min and the temperature was (37±0.5) ° C for dissolution. The sampling time was 5 min, and the filtrate was filtered. The filtrate was used as the test solution, and the dissolution rate was determined by HPLC. The results are shown in Table 1; Table 1 is the dissolution rate determination results of this application (see Figure 1).

[0077] As shown in Table 1, the dapagliflozin tablets prepared by the present invention have high uniformity and can achieve a dissolution rate of 90% in a relatively short period of time. Compared with commercially available dapagliflozin tablets, they have high stability, high dissolution rate and better overall performance.

[0078] The embodiments of the present invention are not limited to the above embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and details, and these are all considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing a dual-release dapagliflozin tablet, characterized in that: The dapagliflozin tablets are composed of an enteric-coated inner core, a gastric-coated middle core, and a coating. The gastric soluble core is composed of the following raw materials in percentage by weight: Composition: 5-7% dapagliflozin, 10% voglibose, 69-73% microcrystalline cellulose complex, 2-4% disintegrant, 10% HPMC coating solution; The enteric-coated inner core is composed of the following raw materials in percentage by weight: Composition: 5~7% dapagliflozin, 8% guanidine sugar, 63~77% microcrystalline cellulose complex, 4~8% disintegrant, 8% HPMC coating solution, and 6% alginic acid.

2. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 1, characterized in that: The method comprises the following steps: S1: The raw material dapagliflozin is crushed and sieved, and then mixed with voglibose, microcrystalline cellulose complex, disintegrant and other excipients. The granules are wet granulated to an average particle size distribution of 0.2 mm to 0.8 mm. The granules are then coated with HPMC coating solution by spraying and dried to obtain dapagliflozin gastric-soluble fine granules. S2: The raw material dapagliflozin is crushed and sieved, and then mixed with excipients such as guanidine sugar, microcrystalline cellulose complex, and disintegrants. The granules are wet granulated to an average particle size of 0.2 mm to 0.8 mm. The granules are then coated with HPMCP coating solution by spraying and dried to obtain dapagliflozin enteric-coated fine granules. S3: tableting the dapagliflozin enteric-coated fine granules prepared in step S2, coating the tablets with an aqueous solution of alginic acid by dipping, and drying to obtain the dapagliflozin enteric-coated core; S4: The dapagliflozin enteric-coated core prepared in step S3 is wrapped with the dapagliflozin gastric-soluble fine particles prepared in step S1 to form a gastric-soluble middle core and tablets are compressed. The tablets are coated with a gelatin solution by dipping to prepare dapagliflozin tablets.

3. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 2, characterized in that: The microcrystalline cellulose complex is one of a lactose microcrystalline cellulose complex and a silicified microcrystalline cellulose complex.

4. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 3, characterized in that: In the lactose-microcrystalline cellulose composite, the weight ratio of lactose to microcrystalline cellulose is 70-75:25-30; in the silicified microcrystalline cellulose composite, the weight ratio of silicon dioxide to microcrystalline cellulose is 2:

98.

5. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 4, characterized in that: The raw materials for preparing the HPMC coating solution are 18 g HPMC, 6 g polyethylene glycol, 4 g ethyl cellulose, 10 g montmorillonite, and 650 mL water.

6. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 5, characterized in that: The mass ratio of dapagliflozin gastric-soluble fine granules to dapagliflozin enteric-soluble fine granules in the dapagliflozin tablets is 3:

7.

7. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 6, characterized in that: The disintegrant is one of cross-linked carboxymethyl cellulose sodium or cross-linked polyvinylpyrrolidone.

8. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 7, characterized in that: The silicon dioxide is mesoporous silicon dioxide with a particle diameter of 350-450 nm.

9. The method for preparing a dual sustained-release dapagliflozin tablet according to claim 8, characterized in that: The average particle size of the microcrystalline cellulose composite is 90-150 μm.

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